Interactions of tubulin with potent natural and synthetic analogs of the antimitotic agent combretastatin: A structure-activity study

C. M. Lin, S. B. Singh, P. S. Chu, R. O. Dempcy, J. M. Schmidt, George Pettit, E. Hamel

Research output: Contribution to journalArticle

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Abstract

Combretastatin, an antineoplastic and antimitotic agent, was isolated from the bark of Combretum caffrum [Can. J. Chem. 60: 1374-1376 (1982); Biochem. Pharmacol. 32:3864-3867 (1983)]. Structurally, combretastatin consists of two substituted benzene rings linked by a saturated, hydroxy-substituted two-carbon bridge. A large number of combretastatin analogs have now been synthesized or obtained from C. caffrum. These vary in substituents on the phenyl rings or bridge carbons, bridge length, unsaturation of the bridge (i.e., stilbene derivatives, with the two phenyl rings oriented either cis or trans), and in precise ring structure (two major variants, with the bridge incorporated into a third six-member ring to form a phenanthrene structure or a methyl group eliminated from vicinal methoxy substituents to form a benzodioxole ring). Available analogs (17 natural products and 22 synthetic agents) were examined for antimitotic and cytotoxic activity and for effects on tubulin polymerization and colchicine binding. Nineteen compounds inhibited cell growth by 50% or more at concentrations of 1 μM or less, and 14 inhibited tubulin polymerization by at least 50% at stoichiometric drug concentrations. The most potent cytotoxic agents generally strongly inhibited both tubulin polymerization and the binding of colchicine to tubulin. The most promising compound is the (cis)-stilbene derivative (cis)-1-(3,4,5-trimethoxyphenyl)-2-(3'-hydroxy-4'-methoxyphenyl)ethene, which has been named combretastatin A-4. This compound inhibited cell growth by 50% at 7 nM, inhibited tubulin polymerization by 50% at 2.5 μM ( 1/4 molar equivalent), and competitively inhibited colchicine binding with an apparent K(i) of 0.14 μM.

Original languageEnglish (US)
Pages (from-to)200-208
Number of pages9
JournalMolecular Pharmacology
Volume34
Issue number2
StatePublished - 1988
Externally publishedYes

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Antimitotic Agents
Tubulin
Polymerization
Colchicine
Stilbenes
Combretum
Carbon
Cytotoxins
Growth
Benzene
Biological Products
Antineoplastic Agents
combretastatin
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology

Cite this

Interactions of tubulin with potent natural and synthetic analogs of the antimitotic agent combretastatin : A structure-activity study. / Lin, C. M.; Singh, S. B.; Chu, P. S.; Dempcy, R. O.; Schmidt, J. M.; Pettit, George; Hamel, E.

In: Molecular Pharmacology, Vol. 34, No. 2, 1988, p. 200-208.

Research output: Contribution to journalArticle

Lin, C. M. ; Singh, S. B. ; Chu, P. S. ; Dempcy, R. O. ; Schmidt, J. M. ; Pettit, George ; Hamel, E. / Interactions of tubulin with potent natural and synthetic analogs of the antimitotic agent combretastatin : A structure-activity study. In: Molecular Pharmacology. 1988 ; Vol. 34, No. 2. pp. 200-208.
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abstract = "Combretastatin, an antineoplastic and antimitotic agent, was isolated from the bark of Combretum caffrum [Can. J. Chem. 60: 1374-1376 (1982); Biochem. Pharmacol. 32:3864-3867 (1983)]. Structurally, combretastatin consists of two substituted benzene rings linked by a saturated, hydroxy-substituted two-carbon bridge. A large number of combretastatin analogs have now been synthesized or obtained from C. caffrum. These vary in substituents on the phenyl rings or bridge carbons, bridge length, unsaturation of the bridge (i.e., stilbene derivatives, with the two phenyl rings oriented either cis or trans), and in precise ring structure (two major variants, with the bridge incorporated into a third six-member ring to form a phenanthrene structure or a methyl group eliminated from vicinal methoxy substituents to form a benzodioxole ring). Available analogs (17 natural products and 22 synthetic agents) were examined for antimitotic and cytotoxic activity and for effects on tubulin polymerization and colchicine binding. Nineteen compounds inhibited cell growth by 50{\%} or more at concentrations of 1 μM or less, and 14 inhibited tubulin polymerization by at least 50{\%} at stoichiometric drug concentrations. The most potent cytotoxic agents generally strongly inhibited both tubulin polymerization and the binding of colchicine to tubulin. The most promising compound is the (cis)-stilbene derivative (cis)-1-(3,4,5-trimethoxyphenyl)-2-(3'-hydroxy-4'-methoxyphenyl)ethene, which has been named combretastatin A-4. This compound inhibited cell growth by 50{\%} at 7 nM, inhibited tubulin polymerization by 50{\%} at 2.5 μM ( 1/4 molar equivalent), and competitively inhibited colchicine binding with an apparent K(i) of 0.14 μM.",
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